Functional Tolerance to Islet Allografts

描述（由申请人提供）：自身免疫性疾病如1型糖尿病（T1D）在临床上表现为产生胰岛素的细胞已经完全丢失。目前，治疗糖尿病的唯一方法就是替换这些产生胰岛素的细胞。然而，接受此类移植物的患者终生遭受免疫抑制治疗，导致感染倾向增加。如果是功能性阻力。-由于同种异体移植物可产生排斥反应，免疫抑制的需求将被避免，从而大大提高接受同种异体移植物的生活质量。在这个探索性的R21应用中，我们提出了一个新的假说来诱导对异体胰岛移植排斥的抵抗。由于这些移植物被浸润细胞产生的细胞因子破坏，我们建议设计对这些致病细胞因子无反应的胰岛。在这个应用中提出了两种不同的实验设计。在第一组研究中，我们将确定靶向表达SOCS-1（一种抑制干扰素信号传导的蛋白质）是否可以改善移植物反应。我们提出了令人信服的初步数据，表明这一目标是可行的，并显示出有希望的结果。在第二组研究中，我们计划下调SOCS-3基因表达，以确定IL-6反应的调节，以及IL-10反应的增加，是否可以在移植物存活中发挥促进生存的作用。广泛的机制研究，以了解系统和局部同种异体移植物反应，提出了每个范例。这些研究将为诱导对同种异体胰岛移植排斥反应的抵抗提供新的方法。

DESCRIPTION (provided by applicant): Autoimmune diseases such as Type 1 diabetes (T1D) manifest themselves clinically when insulin producing cells are already completely lost. At this point, the only cure for diabetes is the replacement of these insulin-producing cells. However, patients receiving such grafts suffer from lifetime immunosuppressive treatments, leading to increased propensity to infection. If functional resistance.- to allograft rejection could be conferred on these grafts the requirement for immunosuppression would be avoided aid the quality of life for those receiving allografts would be greatly enhanced. In this exploratory R21 application we propose a new hypothesis for the induction of resistance to islet allograft rejection. Since these grafts are destroyed by cytokines produced by infiltrating cells, we proposed to engineer islets that are unresponsive to these pathogenic cytokines. Two different experimental designs are proposed in this application. In the first set of studies we will determine whether targeted expression of SOCS-1, a protein that inhibits interferon signaling, can ameliorate graft responses. We present compelling preliminary data stating that this aim is feasible and shows promising results. In the second set of studies we plan to down-modulate SOCS-3 gene expression to determine if modulation of IL-6 responses, with increased responses to IL-10, could play a pro-survival role in graft survival. Extensive mechanistic studies, to understand both systemic and localized allograft responses, are proposed for each paradigm. These studies should lead to new methods for inducing resistance to islet allograft rejection.